Cancer results from the disregulation of signaling pathways that control cell growth and cell death. Prostate diseases, including benign prostate hyperplasia and prostate cancer, are the leading malignancies affecting males in the United States and abroad. Factors responsible for the initiation and/or progression of both benign and malignant growth of the prostate remain poorly understood, although androgens and peptide growth factors have been implicated. The novel hypothesis that G proteins contribute to the neoplastic growth and metastasis of the prostate is supported by our recent findings that activation of G protein-coupled receptors for lysophosphatidic acid (LPA) results in increased mitogenic signaling, growth and invasion of cultured prostate cancer cells, and transactivation of the epidermal growth factor and androgen receptors. Further support to this hypothesis is the finding that pertussis toxin, a pharmacologic inhibitor of Gi/o proteins, inhibits the growth and metastasis of prostate cancer PC-3 cells injected into nude mice. Although clearly involved, the mechanisms by which G proteins contribute to growth and metastasis of prostate cancer cells are not known. The central hypothesis of this proposal is that LPA activates a pool of G proteins that mediate the transduction of growth and metastatic signals in prostate cancer cells. Experiments will focus principally on the biochemical and pharmacological properties of LPA-mediated mitogenic signal transduction pathways in prostate cancer cells. The specific aims are: [1] To determine the effect of LPA stimulation on prostate cell growth and motility using in vitro model systems; [2] To determine the role of specific LPA receptor subtypes in the growth and motility of prostate cells; [3] To identify the specific role of Galpha and Gbetagamma subunits in the LPA- regulated activation of ERK and androgen receptor in prostate cancer cells. The successful conclusion of these proposed studies will provide needed information to rationally develop novel and effective strategies for the control of prostate cancer in humans.